CN110664760B - VEGFR targeted inhibitor loaded drug carrier and preparation method and application thereof - Google Patents
VEGFR targeted inhibitor loaded drug carrier and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a VEGFR targeted inhibitor loaded drug carrier, which comprises a zeolite imidazole framework and a VEGFR targeted inhibitor embedded in the zeolite imidazole framework. The invention also discloses a preparation method of the VEGFR targeted inhibitor-loaded drug carrier, which comprises the following steps: and encapsulating the VEGFR targeted inhibitor in a zeolite imidazole framework by an in-situ embedding method to obtain the VEGFR targeted inhibitor-zeolite imidazole framework carrier. The invention also discloses application of the medicine carrier of the VEGFR targeted inhibitor in preparing anti-tumor treatment medicines. The VEGFR targeted inhibitor-loaded drug carrier improves the physicochemical stability of the VEGFR targeted inhibitor and endows the drug with tumor targeting property, thereby solving the problem of low utilization rate of the VEGFR targeted inhibitor in tumor treatment and reducing the toxic and side effects of drug treatment; the preparation method provided by the invention is simple, and the drug carrier with high-load VEGFR targeted inhibitor can be obtained.
Description
Technical Field
The invention relates to a targeting vector, in particular to a VEGFR targeting inhibitor loaded drug carrier, and a preparation method and application thereof.
Background
Globally, the mortality rate of malignant tumors is high in the disease. Novel treatment modes aiming at tumors need to be researched and developed. Due to the complexity and heterogeneity of malignancies, the targeted therapeutic efficacy of malignancies is still not ideal at present.
The anti-vascular therapy is the core link of the current target therapy of malignant tumors, and the key for solving the bottleneck of the anti-vascular drug therapy is to increase the drug amount in the tumors. At present, many approved drugs applied to targeting drugs of malignant tumors have anti-vascular functions, and VEGFR signal pathways are main targets of the drugs. The VEGFR pathway plays a central regulatory role in angiogenesis and formation and thus plays a critical role in the development of tumors. Therefore, the targeted anti-vascular therapy is an important link of the current clinical targeted therapy of malignant tumors. Regorafenib is a recently approved clinical targeted anti-vascular drug currently available for the treatment of many tumors. Cediranib (cediranib) is also a highly potent VEGFR inhibitor.
However, the efficacy of current single-agent anti-vascular treatments for tumors is not ideal. The anti-vascular strategy of tumor treatment plays a role of 'double-edged sword' to a certain extent, which mainly reflects that the delivery of chemotherapy drugs in tumors is reduced after vascular inhibition, and further the drug concentration in the tumors is reduced. Therefore, increasing the amount of drug inside the tumor is the key to solving the therapeutic bottleneck of the anti-vascular drug.
Medical applications of nanomaterials are one of the current research hotspots. Metal-organic frameworks (MOFs), also known as porous coordination polymers, have relatively good stability and relatively high specific surface area, and are relatively widely studied porous materials in recent years. The metal-organic framework material is generally formed by connecting specific metal ions or metal clusters and corresponding organic ligands through strong coordination bonds and has a certain periodic network structure. The metal-organic framework contains both inorganic metal and organic molecules, and thus has the dual characteristics of inorganic materials and organic materials. As a good drug carrier, the metal organic framework material zeolite imidazole ester framework (ZIF-8) also has the characteristic of pH response. Since ZIF-8 is sensitive to an acidic environment and can be selectively degraded in the acidic environment, and tumor tissues often have the acidic environment, ZIF-8 has a passive targeting effect on the tumor tissues. Therefore, the pH responsive nano drug delivery system based on ZIF-8 can lead the chemotherapeutic drug to obtain tumor targeting, thereby promoting the drug to be concentrated in tumor tissues and improving the drug treatment effect.
In conclusion, the single-drug anti-vascular therapy effect of the tumor is not ideal; increasing the concentration of the drug inside the tumor is the key to solve the bottleneck of the anti-vascular targeted therapy of the liver cancer; the ZIF-8 nano drug delivery system can effectively improve the concentration of the drug in the tumor; based on the ZIF-8 nano drug delivery system, the drug targeting property can be given, the problem of reduced delivery of tumor-targeted anti-vascular drugs caused by chemotherapy in tumors is solved in a targeted manner, and the treatment effect is enhanced.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a VEGFR targeted inhibitor loaded drug carrier and a preparation method thereof, which improve the physicochemical stability of the VEGFR targeted inhibitor and endow the drug with tumor targeting property, thereby solving the problem of low utilization rate of the VEGFR targeted inhibitor in tumor treatment and reducing the toxic and side effects of the drug treatment; the preparation method provided by the invention is simple, and the drug carrier with high-load VEGFR targeted inhibitor can be obtained.
The technical scheme provided by the invention is as follows:
a VEGFR targeted inhibitor-loaded drug carrier (targeted carrier) comprises a zeolite imidazole framework and a VEGFR targeted inhibitor embedded in the zeolite imidazole framework.
Preferably, the VEGFR targeted inhibitor is regorafenib or cediranib.
Preferably, the loading amount of the regorafenib or cediranib in the drug carrier is 18-20%.
The VEGFR targeted inhibitor is encapsulated in a zeolite imidazole framework by an in-situ embedding method. The VEGFR targeted inhibitor has the capacity of inhibiting the formation of tumor vessels, and the zeolite imidazole skeleton has a protection effect on the VEGFR targeted inhibitor, so that the degradation speed of the VEGFR targeted inhibitor at non-tumor parts in vivo can be slowed down, and the time of the VEGFR targeted inhibitor in a blood system at high concentration is prolonged; and secondly, the zeolite imidazole framework carrier has pH targeting property, and the VEGFR targeted inhibitor is encapsulated in the zeolite imidazole framework, so that the zeolite imidazole framework carrier has targeting property for tumor tissues, can be selectively degraded in tumor tissue parts, targets tumor cells and can protect normal cells.
The invention also provides a preparation method of the VEGFR targeted inhibitor loaded drug carrier, which is characterized in that the VEGFR targeted inhibitor is encapsulated in the zeolite imidazole skeleton by an in-situ embedding method to obtain the VEGFR targeted inhibitor-zeolite imidazole skeleton carrier (the VEGFR targeted inhibitor loaded drug carrier).
Preferably, regorafenib (marked as REG) is encapsulated in a zeolite imidazole framework (ZIF-8) by an in-situ embedding method to obtain a regorafenib-zeolite imidazole framework vector (marked as REG @ ZIF-8);
preferably, cediranib (marked as CED) is encapsulated in a zeolite imidazole framework (ZIF-8) by an in-situ embedding method to obtain a cediranib-zeolite imidazole framework carrier (marked as CED @ ZIF-8);
the preparation method provided by the invention is simple in synthesis method, and the loading capacity of regorafenib or cediranib in the prepared drug carrier is 18-20%, so that the utilization rate and the drug effect of the drug are improved.
Preferably, the in situ embedding method comprises:
reacting zinc nitrate with a VEGFR targeted inhibitor to form a coordination compound;
and reacting the coordination compound with 2-methylimidazole to obtain the VEGFR targeted inhibitor-zeolite imidazole framework carrier.
Preferably, the in situ embedding method comprises:
respectively preparing zinc nitrate and a VEGFR targeted inhibitor into methanol solutions, and mixing at room temperature to obtain a coordination compound system; further preferably, the mixing means stirring for 1-5 min; the mass ratio of the VEGFR targeted inhibitor to the zinc nitrate to the anhydrous methanol is 1-10: 1-100: 100, respectively;
and adding a methanol solution of 2-methylimidazole into the coordination compound system, mixing at room temperature, centrifuging, cleaning and drying to obtain the VEGFR targeted inhibitor-zeolite imidazole framework carrier.
Further preferably, the mixing means stirring for 15-20 min; the feeding ratio of the 2-methylimidazole to the anhydrous methanol is 2-5g:10 ml.
Preferably, the mass ratio of the VEGFR targeted inhibitor to the zinc nitrate to the 2-methylimidazole is 1-10:10-50: 20-200.
Preferably, the mass ratio of the VEGFR targeted inhibitor to the zinc nitrate to the 2-methylimidazole is 1:5-20: 50-200.
The invention also provides application of the VEGFR targeted inhibitor loaded drug carrier in antitumor treatment.
Compared with the prior art, the invention has the beneficial effects that:
(1) the zeolite imidazole skeleton has a protective effect on VEGFR targeted inhibitors, and can slow down the degradation speed of the drugs at non-tumor parts in vivo, so that the time of high concentration of the drugs in a blood system is prolonged.
(2) The zeolite imidazole skeleton has the diameter of 10-500nm, can enter cells through endocytosis of cell membranes, has stable structure, can be discharged through human metabolism, and has no cytotoxicity; ZIF-8 has huge specific surface area and pore volume, thereby having larger drug-loading capacity and having drug slow-release function due to the special pore channel structure.
(3) According to the invention, the zeolite imidazole framework carrier has pH targeting property, and the VEGFR targeted inhibitor is encapsulated in the zeolite imidazole framework, so that the zeolite imidazole framework carrier has targeting property for tumor tissues, can be selectively degraded in tumor tissue parts, is targeted to tumor cells, and aims at solving the problem of reduced delivery of tumor-targeted antiangiogenic drugs in tumors and enhancing the tumor treatment effect.
Drawings
FIG. 1 is a UV spectrum of REG @ ZIF-8 prepared in example 1;
FIG. 2 is a UV spectrum of CED @ ZIF-8 prepared in example 2;
FIG. 3 is an infrared spectrum of REG @ ZIF-8 prepared in example 1;
FIG. 4 is an infrared spectrum of CED @ ZIF-8 prepared in example 2;
FIGS. 5 (a) and (b) are a scanning electron micrograph and a transmission electron micrograph, respectively, of REG @ ZIF-8 prepared in example 1;
FIGS. 6 (a) and (b) are a scanning electron micrograph and a transmission electron micrograph, respectively, of CED @ ZIF-8 prepared in example 1;
FIG. 7 is an XRD pattern of REG @ ZIF-8 prepared in example 1;
FIG. 8 is an XRD pattern of CED @ ZIF-8 prepared in example 2;
FIG. 9 is a graph of the drug release profile of REG @ ZIF-8 prepared in example 1 at various pH;
FIG. 10 is a graph of the drug release profile of CED @ ZIF-8 prepared in example 2 at various pHs;
FIG. 11 is a graph showing cytotoxicity test of REG @ ZIF-8 prepared in example 1 under neutral environment (pH 7.4);
FIG. 12 is a graph showing cytotoxicity test of CED @ ZIF-8 prepared in example 2 under neutral environment (pH 7.4).
Detailed Description
The present invention is further illustrated by the following specific examples.
Example 1: preparation of REG @ ZIF-8
(1) 40mg of REG was dissolved in 4ml of methanol and 0.2g of zinc nitrate hexahydrate was dissolved in 0.8ml of methanol, and stirred at room temperature for 5min to form a coordinate bond with REG using zinc ions of zinc nitrate;
(2) adding 10ml of anhydrous methanol and 2g of 2-methylimidazole, and continuously stirring for 15min at room temperature to form ZIF-8 by the 2-methylimidazole and zinc ions of the coordination compound;
(3) centrifuging at the rotating speed of 11000rmp for 20min, washing with a mixed solution of absolute ethyl alcohol and deionized water for three times respectively to remove unreacted reagents, and drying in vacuum to obtain the REG @ ZIF-8 carrier;
the REG loading in the REG @ ZIF-8 vector prepared in example 1 was 19.85%.
Example 2: preparation of CED @ ZIF-8
(1) Dissolving 10mg CED in 4ml methanol and 0.2g zinc nitrate hexahydrate in 0.8ml methanol, mixing, stirring at room temperature for 5min, and forming coordination bond with zinc ion of zinc nitrate and CED;
(2) adding 10ml of anhydrous methanol and 2g of 2-methylimidazole, and continuously stirring for 15min at room temperature to form ZIF-8 by the 2-methylimidazole and zinc ions of the coordination compound;
(3) centrifuging for 20min at the rotating speed of 11000rmp, washing for three times by using a mixed solution of absolute ethyl alcohol and deionized water respectively to remove unreacted reagents, and drying in vacuum to obtain a CED @ ZIF-8 carrier;
the loading of CED in the CED @ ZIF-8 vector prepared in example 2 was 18.96%.
Characterization test 1: ultraviolet spectral detection
The UV spectrum of the supernatant was measured by dissolving dried REG @ ZIF-8 (prepared in example 1) and REG in PBS buffer. The ultraviolet spectra (UV/vis) are shown in FIG. 1. As can be seen from FIG. 1, the characteristic absorption peak at 210nm of regorafenib does not appear in the ultraviolet spectrum of REG @ ZIF-8. This indicates that regorafenib is embedded within ZIF-8.
The dried CED @ ZIF-8 (prepared in example 2) and CED were dissolved in PBS buffer solution, and the supernatant was tested for UV spectrum. The ultraviolet spectra (UV/vis) are shown in FIG. 2. As can be seen in FIG. 2, the characteristic absorption peak at 236nm for CED does not appear in the UV spectrum of CED @ ZIF-8. This indicates that CED is embedded within ZIF-8.
Characterization test 2: infrared spectroscopy detection
(1) Drying regorafenib, ZIF-8, REG @ ZIF-8 (prepared in example 1), CED, ZIF-8 and CED @ ZIF-8 (prepared in example 2), then placing the dried materials into a mortar, adding a proper amount of KBr slightly exceeding the quality of a drug to be tested, uniformly grinding the mixture until the granularity is less than 2 mu m so as to avoid the influence of scattered light, then placing the mixture into a drier for drying treatment, pressing the mixture into a transparent sheet on an oil press under the pressure of about 40MPa, and measuring the transparent sheet on the oil press;
(2) the infrared spectra (FTIR) are shown in fig. 3 and 4, respectively. The absorption peak at 1721 and the absorption peak at 837 for C-H, characteristic group C ═ O in regorafenib, are shown in fig. 3; the absorption peak at 1420 for the characteristic group-N ═ C-in ZIF-8 is shown in fig. 3; REG @ ZIF-8 possesses an absorption peak at 1420, and there are no absorption peak at 1721 and no absorption peak at 837, indicating that regorafenib is encapsulated inside the vector. The absorption peak at 1231 and the absorption peak at 905 for the characteristic group-C-O-C-in CED are shown in FIG. 4; the absorption peak at 1420 for the characteristic group-N ═ C-in ZIF-8 is shown in fig. 4; REG @ ZIF-8 possesses an absorption peak at 1420, and there are no absorption peaks at 1231 and 905, indicating that CED is encapsulated inside the vector.
Characterization test 3: scanning electron microscope detection and transmission electron microscope detection
The scanning electron micrograph of REG @ ZIF-8 (prepared in example 1) is shown in FIG. 5 (a), and the transmission electron micrograph is shown in FIG. 5 (b); the scanning electron micrograph of CED @ ZIF-8 (prepared in example 2) is shown as (a) in FIG. 6, and the transmission electron micrograph is shown as (b) in FIG. 6.
The electron microscope image shows that the zeolite imidazole skeleton is octahedron and the size is in nanometer level; the ZIF-8 loaded with the drug has obvious octahedral crystal form and is not adhered. The structure of each medicine particle is similar, and the particle size is relatively stable.
Characterization test 4: x-ray diffraction detection
The X-ray diffraction patterns of REG @ ZIF-8 prepared in example 1 and CED @ ZIF-8 prepared in example 2 are shown in FIGS. 7 and 8, and it can be seen from FIGS. 7 and 8 that the ZIF-8 carrier loaded with regorafenib and CED still maintains the crystal structure of the zeolitic imidazoles framework.
Performance test 1: drug release test at different pH
REG @ ZIF-8 (prepared in example 1) and CED @ ZIF-8 (prepared in example 2) were tested for release profiles in liquid environments of different pH. The content of regorafenib in the supernatant is analyzed by ultraviolet light to judge the drug release rate. As shown in fig. 9 and 10. As can be seen from fig. 9 and 10, the drug performance is stable in neutral environment (PBS of pH7.4), and the release rate is significantly increased in acidic environment (PBS of pH6.0 and pH 6.5).
Performance test 2: drug cytotoxicity assay in neutral Environment (pH7.4)
REG @ ZIF-8 (prepared in example 1) and CED @ ZIF-8 (prepared in example 2) were tested for cytotoxicity in a neutral liquid environment (pH7.4, MEM medium). Adopts human liver cancer cell strain HCC-LM3 as object. The killing effect of the drug on cells was analyzed by the CCK-8 assay. As shown in fig. 11 and 12. As can be seen from fig. 11 and 12, the ZIF-8-coated drug was stable in neutral environment, significantly reducing cytotoxicity.
Claims (7)
1. The VEGFR targeted inhibitor-loaded drug carrier is characterized by comprising a zeolite imidazole framework and a VEGFR targeted inhibitor embedded in the zeolite imidazole framework; the VEGFR targeted inhibitor is regorafenib or cediranib.
2. The VEGFR targeted inhibitor loaded pharmaceutical carrier of claim 1, wherein a loading amount of regorafenib or cediranib in the pharmaceutical carrier is 18-20%.
3. The preparation method of the VEGFR targeted inhibitor-loaded drug carrier according to claim 1, wherein the VEGFR targeted inhibitor is encapsulated in a zeolite imidazole framework by an in-situ embedding method to obtain the VEGFR targeted inhibitor-zeolite imidazole framework carrier.
4. The method for preparing a pharmaceutical carrier for a VEGFR targeted inhibitor according to claim 3, wherein the in situ encapsulation method comprises:
reacting zinc nitrate with VEGFR molecular targeted inhibitor to form coordination compound;
and reacting the coordination compound with 2-methylimidazole to obtain the VEGFR targeted inhibitor-zeolite imidazole framework carrier.
5. The method for preparing the VEGFR targeted inhibitor-loaded drug carrier according to claim 3 or 4, wherein the in situ embedding method comprises:
respectively preparing zinc nitrate and VEGFR molecular targeted inhibitor into methanol solutions, and mixing at room temperature to obtain a coordination compound system;
and adding a methanol solution of 2-methylimidazole into the coordination compound system, mixing at room temperature, centrifuging, cleaning and drying to obtain the VEGFR molecular targeted inhibitor-zeolite imidazole framework carrier.
6. The method for preparing the VEGFR targeted inhibitor-loaded drug carrier of claim 4, wherein the mass ratio of the VEGFR targeted inhibitor to the zinc nitrate to the 2-methylimidazole is 1-10:10-50: 20-200.
7. Use of a pharmaceutical carrier of the VEGFR targeted inhibitor of any one of claims 1-2 for the preparation of an anti-tumor therapeutic.
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